Roundabout (gene) - Discovery

Discovery

A large-scale screen of the Drosophila genome for mutants that exhibited axon guidance defects led to the discovery of the roundabout (robo) mutation. In robo mutants, axons were observed to inappropriately cross and recross the midline. It was subsequently found that the secreted protein Slit was the ligand for the Roundabout receptor. Vertebrate Slit proteins were identified shortly after, and were shown to bind both vertebrate and Drosophila Robo receptors and to mediate axonal repulsion of spinal cord explants. It was several more years before a functional analysis of the vertebrate slit and robo mutants was performed; this analysis demonstrated that Slit-Robo signaling regulates commissural axon guidance in vertebrates as well. Interestingly, while the vertebrate receptors Robo1 and Robo2 signal repulsion in response to Slit to prevent inappropriate midline crossing, a novel function for Robo3/Rig1 was discovered; unlike the other Robo receptors, it is required to promote midline crossing. However, the mechanism by which Robo3 promotes midline crossing remains unclear.